Therapeutic substituted piperidone compounds

ABSTRACT

Compounds comprising 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or a prodrug thereof are disclosed herein. Details are provided herein. Compositions, methods, and medicaments related thereto are also disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a national stage application under 35 U.S.C. § 371 of PCTapplication PCT/US2005/039746, filed Nov. 2, 2005, which claims thebenefit of U.S. Provisional Application Ser. No. 60/625,658 filed Nov.4, 2004 and U.S. Provisional Application Ser. No. 60/629,863 filed Nov.19, 2004, each of which is incorporated by reference in their entiretyherein

DESCRIPTION OF RELATED ART

Ocular hypotensive agents are useful in the treatment of a number ofvarious ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

Glaucoma is a disease of the eye characterized by increased intraocularpressure. On the basis of its etiology, glaucoma has been classified asprimary or secondary. For example, primary glaucoma in adults(congenital glaucoma) may be either open-angle or acute or chronicangle-closure. Secondary glaucoma results from pre-existing oculardiseases such as uveitis, intraocular tumor or an enlarged cataract.

The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupilary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe, and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

Considering all types together, glaucoma occurs in about 2% of allpersons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical β-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

Certain eicosanoids and their derivatives are currently commerciallyavailable for use in glaucoma management. Eicosanoids and derivativesinclude numerous biologically important compounds such as prostaglandinsand their derivatives. Prostaglandins can be described as derivatives ofprostanoic acid which have the following structural formula:

Various types of prostaglandins are known, depending on the structureand substituents carried on the alicyclic ring of the prostanoic acidskeleton. Further classification is based on the number of unsaturatedbonds in the side chain indicated by numerical subscripts after thegeneric type of prostaglandin [e.g. prostaglandin E₁ (PGE₁),prostaglandin E₂ (PGE₂)], and on the configuration of the substituentson the alicyclic ring indicated by α or β [e.g. prostaglandin F_(2α)(PGF_(2β))].

WO2004085430 and United States Patent Application Publication No.2004/0198701 disclose compounds such as the one shown below.

United States Patent Application Publication 2004/0142969 andWO2004063158 disclose compounds such as the one shown below.

U.S. Pat. No. 6,747,037; U.S. patent application Ser. No. 763,702, filedJan. 22, 2004; U.S. Patent Provisional Application Ser. No. 577,361,filed Jun. 4, 2004; and U.S. patent application Ser. No. 861,957, filedon Jun. 3, 2004; all of which are expressly incorporated by referenceherein, disclose other compounds of interest.

Inflammatory bowel disease (IBD) is a group of disease characterized byinflammation in the large or small intestines and is manifest insymptoms such as diarrhea, pain, and weight loss.

Nonsteroidal anti-inflammatory drugs have been shown to be associatedwith the risk of developing IBD, and recently Kabashima and colleagueshave disclosed that “EP4 works to keep mucosal integrity, to suppressthe innate immunity, and to downregulate the proliferation andactivation of CD4+ T cells. These findings have not only elucidated themechanisms of IBD by NSAIDs, but also indicated the therapeuticpotential of EP4-selective agonists in prevention and treatment of IBD.”(Kabashima, et. al., The Journal of Clinical Investigation, April 2002,Vol. 9, 883-893)

Prostaglandin EP₄ selective agonists are believed to have several othermedical uses. For example, U.S. Pat. No. 6,552,067 B2 teaches the use ofprostaglandin EP4 selective agonists for the treatment of “methods oftreating conditions which present with low bone mass, particularlyosteoporosis, frailty, an osteoporotic fracture, a bone defect,childhood idiopathic bone loss, alveolar bone loss, mandibular boneloss, bone fracture, osteotomy, bone loss associated with periodontitis,or prosthetic ingrowth in a mammal”.

U.S. Pat. No. 6,586,468 B1 teaches that prostaglandin EP4 selectiveagonists “are useful for the prophylaxis and/or treatment of immunediseases (autoimmune diseases (amyotrophic lateral sclerosis (ALS),multiple sclerosis, Sjoegren's syndrome, arthritis, rheumatoidarthritis, systemic lupus erythematosus, etc.), post-transplantationgraft rejection, etc.), asthma, abnormal bone formation, neurocytedeath, pulmopathy, hepatopathy, acute hepatitis, nephritis, renalinsufficiency, hypertension, myocardial ischemia, systemic inflammatorysyndrome, pain induced by ambustion, sepsis, hemophagocytosis syndrome,macrophage activation syndrome, Still's diseases, Kawasaki diseases,burn, systemic granuloma, ulcerative colititis, Crohn's diseases,hypercytokinemia at dialysis, multiple organ failure, shock, etc. Theyare also connected with sleeping disorders and platelet coagulations,and therefore they are thought to be useful for these diseases.”

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates one potential synthetic method of preparing thecompounds disclosed herein.

DESCRIPTION OF THE INVENTION

Compounds comprising

or a pharmaceutically acceptable salt or a prodrug thereof are disclosedherein;wherein a dashed line represents the presence or absence of a bond;Y is an organic acid functional group, or an amide or ester thereofcomprising from 0 to 12 carbon atoms; or Y is hydroxymethyl or an etherthereof comprising from 0 to 12 carbon atoms; or Y is a tetrazolylfunctional group;Ar is interarylene or interheteroarylene; andE is hydrocarbyl or heterohydrocarbyl.

Compounds having the stereochemistry shown in the structures below arespecifically contemplated herein.

Pharmaceutically acceptable salts or prodrugs of compounds of thesestructures are also contemplated.

In the structures disclosed herein, a dashed line represents thepresence of absence of a bond. Thus, compounds according to thestructures shown below are contemplated.

Pharmaceutically acceptable salts or prodrugs of compounds of thesestructures are also contemplated.

Interarylene or heterointerarylene refers to an aryl ring or ring systemor a heteroaryl ring or ring system which connects two other parts of amolecule, i.e. the two parts are bonded to the ring in two distinct ringpositions. Interarylene or heterointerarylene may be substituted orunsubstituted. Unsubstituted interarylene or heterointerarylene has nosubstituents other than the two parts of the molecule it connects.Substituted interarylene or heterointerarylene has substitutents inaddition to the two parts of the molecule it connects.

In one embodiment, Ar is substituted or unsubstituted interphenylene,interthienylene, interfurylene, or interpyridinylene. In anotherembodiment Ar is interphenylene, interthienylene, or interfurylene. Inanother embodiment Ar is interphenylene (Ph).

In one embodiment Ar is 1,3-substituted, i.e. the attachment occurs atpositions on the ring having one ring atom in between them.Meta-interphenylene such as when A has the structure shown below, areexamples.

Other examples for include the structures shown below.

Substituents for interarylene or heterointerarylene are the same asthose for aryl or heteroaryl, and will described in detail later herein.

An organic acid functional group is an acidic functional group on anorganic molecule. While not intending to be limiting, organic acidfunctional groups generally comprise an oxide of carbon, sulfur, orphosphorous. Thus, while not intending to limit the scope of theinvention in any way, in certain compounds Y is a carboxylic acid,sulfonic acid, or phosphonic acid functional group, i.e. one of thestructures shown below.

Salts of any of these acids of any pharmaceutically acceptable form arealso contemplated.

Additionally, an amide or ester of one of the organic acids shown abovecomprising from 0 to 12 carbon atoms is also contemplated. In an ester,a hydrocarbyl moiety replaces a hydrogen atom of an acid such as in acarboxylic acid ester, e.g. CO₂R². In an amide, an amine group replacesan OH of the acid. An amine is a moiety with a central nitrogen that hasexactly three bonds to C or H. Examples of amides include CON(R²)₂,CON(OR²)R², CON(CH₂CH₂OH)₂, and CONH(CH₂CH₂OH). Moieties such asCONHSO₂R² are also amides of the carboxylic acid notwithstanding thefact that they may also be considered to be amides of the sulfonic acidR²—SO₃H.

While not intending to limit the scope of the invention in any way, Ymay also be hydroxymethyl or an ether thereof comprising from 0 to 12carbon atoms. Thus, compounds having a structure shown below arepossible.

Additionally, ethers of these compounds are also possible. An ether isdefined as a functional group wherein a hydrogen of an hydroxyl isreplaced by carbon, e.g., Y is CH₂OCH₃, CH₂OCH₂CH₃, etc.

Finally, while not intending to limit the scope of the invention in anyway, Y may be a tetrazolyl functional group, i.e. compounds having astructure such as one of those shown below.

When R² is hydrogen, the tetrazolyl functional group has two tautomericforms, which can rapidly interconvert in aqueous or biological media,and are thus equivalent to one another. These tautomers are shown below.

Additionally, if R² is C₁-C₆ alkyl, phenyl, or biphenyl, other isomericforms of the tetrazolyl functional group such as the one shown below arealso possible, all of these are considered to be within the scope of theterm “tetrazolyl”.

While not intending to limit the scope of the invention in any way, inone embodiment, Y is selected from the group consisting of CO₂(R²),CON(R²)₂, CON(OR²)R², CON(CH₂CH₂OH)₂, CONH(CH₂CH₂OH), CH₂OH, P(O)(OH)₂,CONHSO₂R², SO₂N(R²)₂, SO₂NHR², and tetrazolyl-R²; wherein R² isindependently H, C₁-C₆ alkyl, phenyl, or biphenyl.

E is hydrocarbyl or heterohydrocarbyl.

Hydrocarbyl is a moiety consisting of only carbon and hydrogen, andincludes, but is not limited to alkyl, alkenyl, alkynyl, and the like,and in some cases aryl, and combinations thereof.

Alkyl is hydrocarbyl having no double or triple bonds including:linear alkyl such as methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl,and the like;branched alkyl such as isopropyl, branched butyl isomers (i.e.sec-butyl, tert-butyl, etc), branched pentyl isomers (i.e. isopentyl,etc), branched hexyl isomers, and higher branched alkyl fragments;cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, etc.; and alkyl fragments consisting of both cyclic andnoncyclic components, whether linear or branched, which may be attachedto the remainder of the molecule at any available position includingterminal, internal, or ring carbon atoms.Alkenyl is hydrocarbyl having one or more double bonds including linearalkenyl, branched alkenyl, cyclic alkenyl, and combinations thereof inanalogy to alkyl.Alkynyl is hydrocarbyl having one or more triple bonds including linearalkynyl, branched alkynyl, cyclic alkynyl and combinations thereof inanalogy to alkyl.Aryl is an unsubstituted or substituted aromatic ring or ring systemsuch as phenyl, naphthyl, biphenyl, and the like. Aryl may or may not behydrocarbyl, depending upon whether it has substituents withheteroatoms.Arylalkyl is alkyl which is substituted with aryl. In other words alkylconnects aryl to the remaining part of the molecule. Examples are—CH₂-Phenyl, —CH₂—CH₂-Phenyl, and the like. Arylalkyl may or may not behydrocarbyl, depending upon whether it has substituents withheteroatoms.Unconjugated dienes or polyenes have one or more double bonds which arenot conjugated. They may be linear, branched, or cyclic, or acombination thereof.

Combinations of the above are also possible.

For the compounds disclosed herein, hydrocarbyl having no ring has 12 orfewer carbon atoms, and hydrocarbyl having one or more rings has 18 orfewer carbon atoms.

Heterohydrocarbyl is a moiety comprising heteroalkyl, heteroaryl, orheteroatom substituted aryl, or a combination thereof, either alone orin combination with hydrocarbyl and/or aryl. The following moieties aretypical examples.

Heteroalkyl is alkyl having one or more carbon atoms substituted with Oor S atoms, provided that no carbon has more than 1 covalent bond to Oor S, i.e. there are no C═O, —O—CH₂—O—, —S—CH₂—S—, etc.; and that O andS are only bonded to carbon, i.e. there are no OH, SH, SO₃H, etc.

Heteroatom substituted aryl comprises one or more substituents on thearyl ring or ring system, said substituents comprising one or more atomswhich are not H or C.

Heteroatom substituted arylalkyl comprises one or more substituents onthe aryl ring or ring system, said substituents comprising one or moreatoms which are not H or C.

Heteroaryl is aryl having one or more N, O, or S atoms in the ring, i.e.a ring carbon is substituted by N, O, or S. While not intending to belimiting, examples of heteroaryl include unsubstituted or substitutedthienyl, pyridinyl, furyl, benzothienyl, benzofuryl, imidizololyl,indolyl, and the like.

Heteroarylalkyl is alkyl which is substituted with heteroaryl. In otherwords alkyl connects heteroaryl to the remaining part of the molecule.Examples are CH₂-thienyl, —CH₂CH₂-benzothienyl, and the like.

Heteroarylheteroalkyl is heteroalkyl which is substituted withheteroaryl. In other words heteroalkyl connects heteroaryl to theremaining part of the molecule. Examples are CH₂O-thienyl,—CH₂S-benzothienyl, and the like.

Arylheteroalkyl is heteroalkyl which is substituted with aryl. In otherwords heteroalkyl connects aryl to the remaining part of the molecule.Examples are CH₂O-phenyl, —CH₂S-naphthyl, and the like.

The substituents of aryl or heteroaryl may have up to 12 non-hydrogenatoms each and as many hydrogen atoms as necessary. Thus, while notintending to limit the scope of the invention in any way, thesubstituents may be:

hydrocarbyl, such as alkyl, alkenyl, alkynyl, and the like, andcombinations thereof;hydrocarbyloxy, meaning O-hydrocarbyl such as OCH₃, OCH₂CH₃,O-cyclohexyl, etc, up to 11 carbon atoms;hydroxyhydrocarbyl, meaning hydrocarbyl-OH such as CH₂OH, C(CH₃)₂OH,etc, up to 11 carbon atoms;nitrogen substituents such as NO₂, CN, and the like, includingamino, such as NH₂, NH(CH₂CH₃OH), NHCH₃, and the like up to 11 carbonatoms;carbonyl substituents, such as CO₂H, ester, amide, and the like;halogen, such as chloro, fluoro, bromo, and the likefluorocarbyl, such as CF₃, CF₂CF₃, etc.;phosphorous substituents, such as PO₃ ²⁻, and the like;sulfur substituents, including S-hydrocarbyl, SH, SO₃H, SO₂-hydrocarbyl,SO₃-hydrocarbyl, and the like.

In certain embodiments, the number of non-hydrogen atoms is 6 or less ina substituent. In other embodiments, the number of non-hydrogen atoms is3 or less in a substituent. In other embodiments, the number ofnon-hydrogen atoms on a substituent is 1.

In certain embodiments, the substituents contain only hydrogen, carbon,oxygen, halo, nitrogen, and sulfur. In other embodiments, thesubstituents contain only hydrogen, carbon, oxygen, and halo.

Unless otherwise indicated, references to aryl, heteroaryl, phenyl,thienyl, benzothienyl, and the like are intended to mean both thesubstituted and the unsubstituted moiety.

For the compounds disclosed herein, heterohydrocarbyl having no ring has12 or fewer carbon atoms, and heterohydrocarbyl having one or more ringshas 18 or fewer carbon atoms.

Thus embodiments wherein E is any of the hydrocarbyl orheterohydrocarbyl moieties disclosed herein are contemplated.

In certain embodiments, E is hydrocarbyl having from 1 to 12 carbonatoms. In other embodiments, E is hydrocarbyl having from 1 to 6 carbonatoms. In other embodiments, E is n-pentyl.

In one embodiment E is X-aryl or X-heteroaryl, wherein X is a covalentbond, CH₂, CH₂CH₂, CH₂O, or CH₂S.

In another embodiment E is X-aryl or X-heteroaryl having from 0 to 2substituents, wherein aryl or heteroaryl is monocyclic or bicyclic, andsaid substituents have up to 6 non-hydrogen atoms each; saidnon-hydrogen atoms being selected from the group consisting of carbon,oxygen, sulfur, nitrogen, fluorine, chlorine, and bromine.

In another embodiment E is X-phenyl, X-napthyl, X-thienyl,X-benzothienyl, X-furyl, or X-benzofuryl, which may have up to 2substituents selected from the group consisting or F, Cl, Br, Me, OMe,and CF₃; and wherein X is CH₂ or a covalent bond.

In another embodiment E is CH₂CH₂-(2-thienyl), CH₂CH₂-(3-thienyl),CH₂-(2-thienyl), CH₂-(3-thienyl), CH₂CH₂-(2-(3-chlorobenzothienyl)),CH₂CH₂-(3-benzothienyl), CH₂-(2-(3-chlorobenzothienyl)), orCH₂-(3-benzothienyl).

Another embodiment comprises

or a pharmaceutically acceptable salt or a prod rug thereof;wherein B is aryl or heteroaryl.

Another compound comprises

or a pharmaceutically acceptable salt or a prod rug thereof.

In another embodiment, B is substituted or unsubstituted phenyl,napthyl, thienyl, benzothienyl, furyl, or benzofuryl.

Another compound comprises

or a pharmaceutically acceptable salt or a prod rug thereof;wherein n is 0 or 1; andR¹ is hydrogen, fluoro, chloro, bromo, methyl, methoxy, or CF₃.

Another compound comprises

or a pharmaceutically acceptable salt or a prod rug thereof;wherein n is 0 or 1; andR¹ is hydrogen, fluoro, chloro, bromo, methyl, methoxy, or CF₃.

Another compound comprises

or a pharmaceutically acceptable salt or a prod rug thereof;wherein R¹ is H or Cl.

Another compound comprises

or a pharmaceutically acceptable salt or a prod rug thereof;wherein R¹ is H or Cl.

Other compounds of interest are shown below.

Pharmaceutically acceptable salts and prodrugs of these compounds arealso contemplated.

While not intending to limit the scope of the invention in any way, itis believed that the compound disclosed herein will be selectiveprostaglandin EP₄ agonists.

The compounds disclosed herein are useful for the prevention ortreatment of glaucoma or ocular hypertension in mammals, or for themanufacture of a medicament for the treatment of glaucoma or ocularhypertension. They are also useful for the treatment of those diseasesdisclosed in the art as being amenable to treatment by prostaglandin EP₄agonist, such as the ones listed previously.

A “pharmaceutically acceptable salt” is any salt that retains theactivity of the parent compound and does not impart any additionaldeleterious or untoward effects on the subject to which it isadministered and in the context in which it is administered compared tothe parent compound. A pharmaceutically acceptable salt also refers toany salt which may form in vivo as a result of administration of anacid, another salt, or a prodrug which is converted into an acid orsalt.

Pharmaceutically acceptable salts of acidic functional groups may bederived from organic or inorganic bases. The salt may comprise a mono orpolyvalent ion. Of particular interest are the inorganic ions, lithium,sodium, potassium, calcium, and magnesium. Organic salts may be madewith amines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine,tromethamine and similar molecules. Hydrochloric acid or some otherpharmaceutically acceptable acid may form a salt with a compound thatincludes a basic group, such as an amine or a pyridine ring.

A “prodrug” is a compound which is converted to a therapeutically activecompound after administration, and the term should be interpreted asbroadly herein as is generally understood in the art. While notintending to limit the scope of the invention, conversion may occur byhydrolysis of an ester group or some other biologically labile group.Generally, but not necessarily, a prodrug is inactive or less activethan the therapeutically active compound to which it is converted. Esterprodrugs of the compounds disclosed herein are specificallycontemplated.

An ester may be derived from a carboxylic acid of C1 (i.e. the terminalcarboxylic acid of a natural prostaglandin), or an ester may be derivedfrom a carboxylic acid functional group on another part of the molecule,such as on a phenyl ring. While not intending to be limiting, an estermay be an alkyl ester, an aryl ester, or a heteroaryl ester. The termalkyl has the meaning generally understood by those skilled in the artand refers to linear, branched, or cyclic alkyl moieties. C₁₋₆ alkylesters are particularly useful, where alkyl part of the ester has from 1to 6 carbon atoms and includes, but is not limited to, methyl, ethyl,propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, t-butyl, pentylisomers, hexyl isomers, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and combinations thereof having from 1-6 carbon atoms, etc.

Those skilled in the art will readily understand that for administrationor the manufacture of medicaments the compounds disclosed herein can beadmixed with pharmaceutically acceptable excipients which per se arewell known in the art. Specifically, a drug to be administeredsystemically, it may be confected as a powder, pill, tablet or the like,or as a solution, emulsion, suspension, aerosol, syrup or elixirsuitable for oral or parenteral administration or inhalation.

For solid dosage forms or medicaments, non-toxic solid carriers include,but are not limited to, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, the polyalkylene glycols,talcum, cellulose, glucose, sucrose and magnesium carbonate. The soliddosage forms may be uncoated or they may be coated by known techniquesto delay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the technique described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release. Liquid pharmaceuticallyadministrable dosage forms can, for example, comprise a solution orsuspension of one or more of the presently useful compounds and optionalpharmaceutical adjutants in a carrier, such as for example, water,saline, aqueous dextrose, glycerol, ethanol and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered may also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like. Typical examples of such auxiliary agentsare sodium acetate, sorbitan monolaurate, triethanolamine, sodiumacetate, triethanolamine oleate, etc. Actual methods of preparing suchdosage forms are known, or will be apparent, to those skilled in thisart; for example, see Remington's Pharmaceutical Sciences, MackPublishing Company, Easton, Pa., 16th Edition, 1980. The composition ofthe formulation to be administered, in any event, contains a quantity ofone or more of the presently useful compounds in an amount effective toprovide the desired therapeutic effect.

Parenteral administration is generally characterized by injection,either subcutaneously, intramuscularly or intravenously. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions. Suitable excipients are, forexample, water, saline, dextrose, glycerol, ethanol and the like. Inaddition, if desired, the injectable pharmaceutical compositions to beadministered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like.

The amount of the presently useful compound or compounds administeredis, of course, dependent on the therapeutic effect or effects desired,on the specific mammal being treated, on the severity and nature of themammal's condition, on the manner of administration, on the potency andpharmacodynamics of the particular compound or compounds employed, andon the judgment of the prescribing physician.

One embodiment is a composition comprising a compound, said compositionbeing an aqueous liquid which is formulated for topical ophthalmicadministration, said compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof;wherein a dashed line represents the presence or absence of a bond;Y is an organic acid functional group, or an amide or ester thereofcomprising from 0 to 12 carbon atoms; or Y is hydroxymethyl or an etherthereof comprising from 0 to 12 carbon atoms; or Y is a tetrazolylfunctional group;Ar is interarylene or interheteroarylene; and

E is hydrocarbyl or heterohydrocarbyl. A liquid which is ophthalmicallyacceptable is formulated such that it can be administered topically tothe eye. The comfort should be maximized as much as possible, althoughsometimes formulation considerations (e.g. drug stability) maynecessitate less than optimal comfort. In the case that comfort cannotbe maximized, the liquid should be formulated such that the liquid istolerable to the patient for topical ophthalmic use. Additionally, anophthalmically acceptable liquid should either be packaged for singleuse, or contain a preservative to prevent contamination over multipleuses.

For ophthalmic application, solutions or medicaments are often preparedusing a physiological saline solution as a major vehicle. Ophthalmicsolutions should preferably be maintained at a comfortable pH with anappropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preservatives that may be used in the pharmaceutical compositions of thepresent invention include, but are not limited to, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate andphenylmercuric nitrate. A useful surfactant is, for example, Tween 80.Likewise, various useful vehicles may be used in the ophthalmicpreparations of the present invention. These vehicles include, but arenot limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl celluloseand purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. A useful chelating agent is edetatedisodium, although other chelating agents may also be used in place orin conjunction with it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative  0-0.10 vehicle   0-40 tonicity adjustor   1-10 buffer 0.01-10 pHadjustor q.s. pH 4.5-7.5 antioxidant as needed surfactant as neededpurified water as needed to make 100%

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound disclosed herein are employed. Topicalformulations may generally be comprised of a pharmaceutical carrier,cosolvent, emulsifier, penetration enhancer, preservative system, andemollient.

Treatment of inflammatory bowel disease may be accomplished by theadministration of the compounds described herein to the sufferingmammal. Inflammatory bowel disease describes a variety of diseasescharacterized by inflammation of the bowels including, but not limitedto, ulcerative colitis and Crohn's disease. Treatment may beaccomplished by oral administration, by suppository, or parenteraladministration, or some other suitable method.

One embodiments is a method comprising administering an effective amountof a compound for the maintenance of colonic mucous, said compoundcomprising

or a pharmaceutically acceptable salt or a prodrug thereof;wherein a dashed line represents the presence or absence of a bond;Y is an organic acid functional group, or an amide or ester thereofcomprising from 0 to 12 carbon atoms; or Y is hydroxymethyl or an etherthereof comprising from 0 to 12 carbon atoms; or Y is a tetrazolylfunctional group;Ar is interarylene or interheteroarylene; andE is hydrocarbyl or heterohydrocarbyl.

One embodiment is a method comprising administering an effective amountof a compound for the treatment of an irritable bowel disease, saidcompound comprising

or a pharmaceutically acceptable salt or a prodrug thereof;wherein a dashed line represents the presence or absence of a bond;Y is an organic acid functional group, or an amide or ester thereofcomprising from 0 to 12 carbon atoms; or Y is hydroxymethyl or an etherthereof comprising from 0 to 12 carbon atoms; or Y is a tetrazolylfunctional group;Ar is interarylene or interheteroarylene; andE is hydrocarbyl or heterohydrocarbyl.

In another embodiment, said irritable bowel disease is colitis.

In another embodiment, said irritable bowel disease is Crohn's disease.

While not intending to limit the scope of the invention in any way,delivery of the compounds disclosed herein to the colon via oral dosageforms may be accomplished by any of a number of methods known in theart. For example, reviews by Chourasia and Jain in J Pharm PharmaceutSci 6 (1): 33-66, 2003 and Shareef et. al (AAPS Pharm Sci 2003; 5 (2)Article 17) describe a number of useful methods. While not intending tolimit the scope of the invention in any way these methods include 1)administration of a prodrug, including an azo or a carbohydrate basedprodrug; 2) coating the drug with, or encapsulating or impregnating thedrug into a polymer designed for delivery to the colon, 3) time releaseddelivery of the drug, 4) use of a bioadhesive system; and the like.

While not intending to be bound in any way by theory, it is believedthat intestinal microflora are capable of reductive cleavage of an azobond leaving the two nitrogen atoms as amine functional groups. Whilenot intending to limit the scope of the invention in any way, the azoprodrug approach has been used to deliver to 5-aminosalicylic acidhumans in clinical trials for the treatment of irritable bowel disease.It is also believed that bacteria of the lower GI also have enzymeswhich can digest glycosides, glucuronides, cyclodextrins, dextrans, andother carbohydrates, and ester prodrugs formed from these carbohydrateshave been shown to deliver the parent active drugs selectively to thecolon. For example, in vivo and in vitro studies on rats and guinea pigswith prodrugs of dexamethasone, prednisolone, hydrocortisone, andfludrocortisone, suggest that glycoside conjugates may be useful for thedelivery of steroids to the human colon. Other in vivo studies havesuggested that glucouronide, cyclodextrin, and dextran prodrugs ofsteroids or non-steroidal anti-inflammatory drugs are useful fordelivery of these drugs to the lower GI tract. An amide of salicylicacid and glutamic acid has been shown to be useful for the delivery ofsalicylic acid to the colon of rabbit and dog.

While not intending to limit the scope of the invention in any way,carbohydrate polymers such as amylase, arabinogalactan, chitosan,chondroiton sulfate, dextran, guar gum, pectin, xylin, and the like, orazo-group containing polymers can be used to coat a drug compound, or adrug may be impregnated or encapsulated in the polymer. It is believedthat after oral administration, the polymers remain stable in the upperGI tract, but are digested by the microflora of the lower GI thusreleasing the drug for treatment.

Polymers which are sensitive to pH may also be used since the colon hasa higher pH than the upper GI tract. Such polymers are commerciallyavailable. For example, Rohm Pharmaceuticals, Darmstadt, Germany,markets pH dependent methacrylate based polymers and copolymers whichhave varying solubilities over different pH ranges based upon the numberof free carboxylate groups in the polymer under the tradename Eudragit®.Several Eudragit® dosage forms are currently used to deliver salsalazinefor the treatment of ulcerative colitis and Crohn's disease. Timerelease systems, bioadhesive systems, and other delivery systems havealso been studied.

Synthetic Procedures

The compounds disclosed herein may be prepared by an analogous procedureto that disclosed in U.S. patent application Ser. No. 861,957, filed onJun. 3, 2004 (Example 50, starting p. 81, line 12), which is expresslyincorporated by reference herein. In this procedure, compound 1 issubstituted for ((Z)-4-chloro-but-2-enyloxy)-acetic acid ethyl ester (p.82, line 11), and the remainder of the procedure is carried out asdescribed. Compound 1 may be prepared as disclosed in FIG. 1 byetherification of 3-hydroxymethylphenol (compound 2) with bromoaceticacid methyl ester in the presence of carbonate base to form compound 3,which is worked up and purified according to standard procedures.Compound 3 is treated with iodine, triphenylphosphine, and imidazole,and worked up and purified using standard procedures to obtaincompound 1. A procedure for preparing compound 1 is also disclosed inDE3601248.

Biological Activity

The activity of compounds disclosed herein is tested according to thefollowing procedures.

Radioligand Binding Cells Stably Expressing EP₁, EP₂, EP₄ and FPReceptors

HEK-293 cells stably expressing the human or feline FP receptor, or EP₁,EP₂, or EP₄ receptors are washed with TME buffer, scraped from thebottom of the flasks, and homogenized for 30 sec using a Brinkman PT10/35 polytron. TME buffer is added to achieve a final 40 ml volume inthe centrifuge tubes (the composition of TME is 100 mM TRIS base, 20 mMMgCl₂, 2M EDTA; 10N HCl is added to achieve a pH of 7.4).

The cell homogenate is centrifuged at 19000 r.p.m. for 20 min at 4° C.using a Beckman Ti-60 rotor. The resultant pellet is resuspended in TMEbuffer to give a final 1 mg/ml protein concentration, as determined byBiorad assay. Radioligand binding competition assays vs. [³H-]17 phenylPGF_(2α) (5 nM) are performed in a 100 μl volume for 60 min. Bindingreactions are started by adding plasma membrane fraction. The reactionis terminated by the addition of 4 ml ice-cold TRIS-HCl buffer and rapidfiltration through glass fiber GF/B filters using a Brandel cellharvester. The filters are washed 3 times with ice-cold buffer and ovendried for one hour. Non-specific binding is determined with 10 uMunlabeled 17-phenyl PGF_(2α).

[³H-] PGE₂ (5 nM; specific activity 180 Ci mmol) is used as theradioligand for EP receptors. Binding studies employing EP₁, EP₂, EP₃,EP₄ are performed in duplicate in at least three separate experiments. A200 μl assay volume is used. Incubations are for 60 min at 25° C. andare terminated by the addition of 4 ml of ice-cold 50 mM TRIS-HCl,followed by rapid filtration through Whatman GF/B filters and threeadditional 4 ml washes in a cell harvester (Brandel). Non-specificbinding is determined with 10⁻⁵M of unlabeled PGE₂.

Methods for FLIPR™ Studies (a) Cell Culture

HEK-293 (EBNA) cells, stably expressing one type or subtype ofrecombinant human prostaglandin receptors (prostaglandin receptorsexpressed: hDP/Gqs5; hEP₁; hEP₂/Gqs5; hEP_(3A)/Gqi5; hEP₄/Gqs5; hFP;hIP; hTP), are cultured in 100 mm culture dishes in high-glucose DMEMmedium containing 10% fetal bovine serum, 2 mM 1-glutamine, 250 μg/mlgeneticin (G418) and 200 μg/ml hygromycin B as selection markers, and100 units/ml penicillin G, 100 μg/ml streptomycin and 0.25 μg/mlamphotericin B.

(b) Calcium Signal Studies on the FLIPR™

Cells are seeded at a density of 5×10⁴ cells per well in Biocoat®Poly-D-lysine-coated black-wall, clear-bottom 96-well plates(Becton-Dickinson) and allowed to attach overnight in an incubator at37° C. Cells are then washed two times with HBSS-HEPES buffer (HanksBalanced Salt Solution without bicarbonate and phenol red, 20 mM HEPES,pH 7.4) using a Denley Cellwash plate washer (Labsystems). After 45minutes of dye-loading in the dark, using the calcium-sensitive dyeFluo-4 AM at a final concentration of 2 μM, plates are washed four timeswith HBSS-HEPES buffer to remove excess dye leaving 100 μl in each well.Plates are re-equilibrated to 37° C. for a few minutes.

Cells are excited with an Argon laser at 488 nm, and emission ismeasured through a 510-570 nm bandwidth emission filter (FLIPR™,Molecular Devices, Sunnyvale, Calif.). Drug solution is added in a 50 μlvolume to each well to give the desired final concentration. The peakincrease in fluorescence intensity is recorded for each well. On eachplate, four wells each serve as negative (HBSS-HEPES buffer) andpositive controls (standard agonists: BW245C (hDP); PGE₂ (hEP₁;hEP₂/Gqs5; hEP_(3A)/Gqi5; hEP₄/Gqs5); PGF_(2α) (hFP); carbacyclin (hIP);U-46619 (hTP), depending on receptor). The peak fluorescence change ineach drug-containing well is then expressed relative to the controls.

Compounds are tested in a high-throughput (HTS) orconcentration-response (CoRe) format. In the HTS format, forty-fourcompounds per plate are examined in duplicates at a concentration of10⁻⁵ M. To generate concentration-response curves, four compounds perplate are tested in duplicates in a concentration range between 10⁻⁵ and10⁻¹¹ M. The duplicate values are averaged. In either, HTS or CoReformat each compound is tested on at least 3 separate plates using cellsfrom different passages to give an n≧3.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent for one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same result. Thus, however detailed the foregoing may appear intext, it should not be construed as limiting the overall scope hereof;rather, the ambit of the present invention is to be governed only by thelawful construction of the appended claims.

1. A compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof; wherein adashed line represents the presence or absence of a bond; Y is anorganic acid functional group, or an amide or ester thereof comprisingfrom 0 to 12 carbon atoms; or Y is hydroxymethyl or an ether thereofcomprising from 0 to 12 carbon atoms; or Y is a tetrazolyl functionalgroup; Ar is interarylene or interheteroarylene; and E is hydrocarbyl orheterohydrocarbyl.
 2. The compound of claim 1 wherein Ar comprises1,3-ring substitution.
 3. The compound of claim 2 wherein Ar isinterphenylene, interthienylene, or interfurylene.
 4. The compound ofclaim 3 wherein Ar is 1,3-interphenylene.
 5. The compound of claim 1wherein E is X-aryl or X-heteroaryl, wherein X is a covalent bond, CH₂,CH₂CH₂, CH₂O, or CH₂S.
 6. The compound of claim 5 wherein E is X-phenyl,X-napthyl, X-thienyl, X-benzothienyl, X-furyl, or X-benzofuryl, whichmay have up to 2 substituents selected from the group consisting or F,Cl, Br, Me, OMe, and CF₃; and wherein X is CH₂ or a covalent bond. 7.The compound of claim 6 wherein E is CH₂CH₂-(2-thienyl),CH₂CH₂-(3-thienyl), CH₂-(2-thienyl), CH₂-(3-thienyl),CH₂CH₂-(2-(3-chlorobenzothienyl)), CH₂CH₂-(3-benzothienyl),CH₂-(2-(3-chlorobenzothienyl)), or CH₂-(3-benzothienyl).
 8. The compoundof claim 1 wherein Ar is interphenylene.
 9. The compound of claim 1comprising

or a pharmaceutically acceptable salt or a prod rug thereof; wherein Bis aryl or heteroaryl.
 10. The compound of claim 9 wherein B issubstituted or unsubstituted phenyl, napthyl, thienyl, benzothienyl,furyl, or benzofuryl.
 11. The compound of claim 1 comprising

or a pharmaceutically acceptable salt or a prod rug thereof.
 12. Thecompound of claim 11 wherein B is substituted or unsubstituted phenyl,napthyl, thienyl, benzothienyl, furyl, or benzofuryl.
 13. The compoundof claim 6 comprising

or a pharmaceutically acceptable salt or a prod rug thereof; wherein nis 0 or 1; and R¹ is hydrogen, fluoro, chloro, bromo, methyl, methoxy,or CF₃.
 14. The compound of claim 13 comprising

or a pharmaceutically acceptable salt or a prod rug thereof; wherein R¹is H or Cl.
 15. The compound of claim 13 comprising

or a pharmaceutically acceptable salt or a prod rug thereof; wherein R¹is H or Cl.
 16. The compound of claim 1 wherein Y is The compound ofclaim 1 wherein Y is selected from the group consisting of CO₂R, CONR₂,CON(OR)R, CON(CH₂CH₂OH)₂, CONH(CH₂CH₂OH), CH₂OH, P(O)(OH)₂, CONHSO₂R,SO₂NR₂, SO₂NHR, and tetrazolyl-R; wherein R is independently H, C₁-C₆alkyl phenyl, or biphenyl.
 17. A method comprising administering aneffective amount of a compound to a mammal for the treatment orprevention of glaucoma or ocular hypertension, said compound comprising

or a pharmaceutically acceptable salt or a prod rug thereof; wherein adashed line represents the presence or absence of a bond; Y is anorganic acid functional group, or an amide or ester thereof comprisingfrom 0 to 12 carbon atoms; or Y is hydroxymethyl or an ether thereofcomprising from 0 to 12 carbon atoms; or Y is a tetrazolyl functionalgroup; Ar is interarylene or interheteroarylene; and E is hydrocarbyl orheterohydrocarbyl.
 18. A method comprising administering an effectiveamount of a compound for the treatment of an irritable bowel disease,said compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof; wherein adashed line represents the presence or absence of a bond; Y is anorganic acid functional group, or an amide or ester thereof comprisingfrom 0 to 12 carbon atoms; or Y is hydroxymethyl or an ether thereofcomprising from 0 to 12 carbon atoms; or Y is a tetrazolyl functionalgroup; Ar is interarylene or interheteroarylene; and E is hydrocarbyl orheterohydrocarbyl.
 19. The method of claim 18 wherein said irritablebowel disease is colitis.
 20. The method of claim 18 wherein saidirritable bowel disease is Crohn's disease.